The vertebrate immune system is composed of a combination of cells and molecules with specialized roles in defending against infecting pathogens such as bacteria, viruses, fungi, and parasites. There are two fundamentally different types of immune responses to infecting pathogens. Acquired immune responses are mediated by highly specialized, systemic cells which recognize pathogens and generate specific immune responses against them. The acquired immune response provides the vertebrate immune system with the ability to remember specific pathogens, and mount stronger responses upon each repeat pathogen exposure. The generation of acquired immunity takes time however (e.g. 2-3 days post infection), which could leave the body susceptible to the early effects of infection where it not for the innate immune system.
Unlike the acquired immune system, the innate immune system does not confer long-lasting or protective immunity. Rather, the innate immune system provides the body with a first line of defense by recognizing and responding to conserved features of pathogens in a generic way. During an innate immune response, an invading pathogen is recognized by several types of dedicated receptors in the host, including soluble receptors in the blood, and membrane-bound, germline-encoded receptors on the surface of host cells. Stimulation of these membrane-bound receptors, known as Toll-like receptors (TLRs), leads to activation of the transcription factor NF-κB and other signaling molecules that are involved in regulating the expression of cytokine genes, including those encoding TNF-α, IL-1, and certain chemokines.
TLRs are pattern recognition receptors that recognize pathogen-derived macromolecules such as bacterial and yeast cell wall components, and viral and bacterial nucleic acids. The conserved features of pathogens recognized by TLRs are collectively referred to as pathogen-associated molecular patterns (PAMPs). In humans, 11 TLRs respond to a variety of PAMPs, including lipopolysaccharides (TLR4), lipopeptides (TLR2 associated with TLR1 or TLR6), bacterial flagellin (TLR5), viral dsRNA (TLR3), viral or bacterial ssRNA (TLRs 7 and 8), and CpG-rich unmethylated DNA (TLR9), among others.
Because of their ability to initiate and propagate inflammation, TLRs are attractive targets for anti-inflammatory agents. Evidence that TLRs are potential therapeutic targets include overexpression in disease, knockout mice being resistant to disease in disease models, ligands exacerbating inflammation in disease models and genetic differences in TLRs or their signaling proteins correlating with risk of disease. Because TLR activation occurs early in the inflammation cascade, there is potentially an advantage in blocking TLRs.
It has been demonstrated that the cytokine response to human cytomegalovirus (CMV, lymphocytic choriomeningitis virus (LCMV), and herpes simplex virus (HSV-1) is controlled by the TLR1/2 complex. TLR1/2 has been suggested to have beneficial effects in both chronic and acute inflammatory diseases ranging from acne to sepsis, and may also uttenuate pulmonary tumor metastases. While several TLR2 antagonists are currently being developed as therapeutics for cancer and autoimmune disease, these antagonists are all naturally derived. Synthetic low molecular weight compounds with inhibitory activity against TLR 1/2 have not yet been described.